INFLUENCE OF WATER ACTIVITY IN ORGANIC-SOLVENT PLUS WATER MIXTURES ONTHE NATURE OF THE CRYSTALLIZING DRUG PHASE .1. THEOPHYLLINE

The hydration state of a hydrate depends on the water activity, a(w), in the crystallization medium. Selection of an appropriate ratio of wa ter to cosolvent in the crystallization medium of a hydrate is critica l and is often semi-empirical. This study attempts to elucidate this s election process by studying the conditions of physical stability of t he solid phases of theophylline, which comprise an anhydrate and a mon ohydrate. A mixture of the anhydrate and the monohydrate may sometimes be obtained, if the system is not in equilibrium. The excess solid ph ase was characterized by powder X-ray diffractometry and the water con tent was measured by Karl-Fischer titrimetry. In contact with methanol + water or 2-propanol (isopropyl alcohol, IPA) + water mixtures, at a (w) < 0.25. the anhydrate was the only solid phase at equilibrium no m atter which solid form was initially added. At a(w) > 0.25 in either s olvent mixture, the monohydrate was obtained as the most stable format equilibrium. These results suggest (a) that water activity is the maj or factor determining the nature of the solid phase of theophylline wh ich crystallizes from methanol + water or IPA + water mixtures and (b) that the system, theophylline anhydrate reversible arrow theophylline monohydrate, is in equilibrium at a(w) = 0.25 and at 25 degrees C. Th e solubilities of the two solid forms in each of the mixed solvent sys tems were also measured and are discussed. The concepts presented. tes ted and discussed may, in principle, be applied to any pharmaceutical system consisting of an anhydrate and a hydrate, or a lower hydrate an d a higher hydrate.